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The Neurobiology of Addiction

Jodi Gilman, Ph.D.

Center for Addiction Medicine

Massachusetts General Hospital

Associate Professor, Department of Psychiatry

Harvard Medical School

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What is Addiction?

• commonly associated with a chronic, relapsing course

• Drug addiction is a chronically relapsing disorder that has been characterized by

– (1) compulsion to seek and take the drug,

– (2) loss of control in limiting intake, and

– (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented

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How Common is Addiction?

• 15.6% (29 million): nonmedical or illicit drug use at some time in their lives

• 2.9% (5.4 million): substance dependence on illicit drugs

• 7.7% (18 million): meet the criteria for abuse or dependence on Alcohol.

• 28.6% (70.9 million): current (past month) users of a tobacco product

• 48% (>100 million): report having used marijuana at some time in their life

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Addiction Involves Multiple Factors

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Addiction is Like Other Diseases…

➢ It is preventable➢ It is treatable➢ It changes biology➢ If untreated, it can last a lifetime

Healthy Brain Diseased Heart

Decreased Heart Metabolism in Heart Disease Patient

Decreased Brain Metabolism in Cocaine-addiction Patient

Diseased Brain/Cocaine Abuse

Healthy Heart

High

Low

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Advances in science have revolutionized our fundamental

views of drug abuse and addiction.

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Your Brain on Drugs in the 1980’s

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Today’s Talk

• Who gets Addicted?

• The Addiction Cycle

–Role of Dopamine/Reward in Addiction

–Role of Impaired Inhibition in Addiction

• Changes in the Brain that Occur

• Treatment and Recovery

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Why do some people

become addicted to drugs

while others do not?

Vulnerability

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Individual Variability

• Inhibitory control abnormalities? Reward Responsivness/Anhedonia? Stress sensitivity Resilience?

• Mood, anxiety, psychotic disorders are clear risk factors

• Those with schizophrenia have cognitive impairments such as diminished prefrontal cortical control over behavior and increased limbic drive similar to those with addictions, perhaps conferring dual risk

• 40-60% of the risk for addiction attributed to genetic factors.

• Genetic factors also present in treatment response

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Who is Predisposed to Addiction?

• The Marshmallow Test: Behavioral and Neural Correlates of Ability to Delay Gratification: 40 Years Later

• 4 year-olds who were able to resist eating one marshmallow in exchange for two marshmallows 15 minutes later showed lower rates of substance use 40 years later.

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high

low

High DA receptor

Low DA receptor

Individual Differences in Response to Drugs:

DA Receptors influence drug liking

As a group, subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant

Adapted from Volkow et al., Am. J. Psychiatry, 1999.

www.mghcme.orgNational Epidemiologic Survey on Alcohol and Related Conditions, 2003.

Age

0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

1.6%

1.8%

5 10 15 21 25 30 35 40 45 50 55 60 65

% in

eac

h a

ge g

rou

p w

ho

d

evel

op

fir

st-t

ime

dep

end

ence

CANNABISALCOHOL

TOBACCO

Addiction is a Developmental Disease that starts in adolescence and childhood

Age at tobacco, alcohol, and cannabis dependence per DSM IV

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What Other Biological Factors Contribute to Addiction--Comorbidity

Prevalence of Drug Disorders

Per

cen

t

Prevalence of Nicotine Addiction

0

20

40

60

80

Per

cen

t

0

5

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40

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Why do Mental Illnesses and Substance Abuse Co-occur?

• Self-medication– substance abuse begins as an

attempt to alleviate symptoms of mental illness

• Causal effects – Substance abuse may increase

vulnerability to mental illness

• Common or correlated causes – the risk factors that give rise to

mental illness and substance abuse may be related or overlap

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• Nonmedical Use

Source: Anthony et al. Exp. Clin. Psychopharmacol. 2(3), pp 244-268 (1994)

**

Pe

rce

nt o

f u

se

rs w

ho

Be

co

me

ad

dic

ted Comparative Prevalence of

Dependence

Among Different Drug Users

0

5

10

15

20

25

30

35

Addictiveness by Drug Type

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Cannabis in the 1960’s-2000’s: THC 1-3%

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Cannabis today: THC 80%

Meier, 2017; Raber et al., 2015

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Borodovsky et al., 2016; Schauer, King et al., 2016; Wang et al., 2016; Weiss, 2015

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– Marijuana growers have worked to make the drug as potent as possible.

– In 1960s-70s average THC concentrations were 1-2%. Today, they are as high as 25%

Marijuana Potency is Increasing

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Sem

antic

Ser

ial

Tota

l

Sem

antic

Ser

ial

Tota

l

Sem

antic

Ser

ial

Tota

l0

1

2

3

4

5

Learning Strategy

Str

ate

gy S

core

Controls Late-onset MJ users Early-onset MJ users

Semantic

clustering is

the ideal

learning

strategy

Marijuana Users, especially those who use before the age of 16, do not learn as much, or as efficiently, as non-users

Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Delay

8

10

12

14

16

Num

ber

of W

ord

s R

ecalle

d fro

m L

ist

Non-users

Early Onset MJ users (<16)Late Onset MJ users (>16)

Early-onset users recall fewer words initally, and never catch up!

SOURCES: Schuster and Gilman et al, 2016, Neuropsychology

Cannabis and Learning

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Stopping cannabis use in adolescents is associated with improved memory after 1 week

0 1 2 3 4-0.1

0.0

0.1

0.2

0.3

0.4

WeekM

em

ory

Score

s Those who stop using improved!

Those who continued use did not improve

Base

line

2-3

day

s4-5

day

s

Wee

k 1

Wee

k 2

Wee

k 3

Wee

k 4

Time Since Stopping Uuse

Abstinent

Control

Mo

re T

HC

This group continued to use

This group stopped MJ use

SOURCES: Schuster and Gilman et al, 2018, Journal of Clinical Psychiatry

Cannabis and Learning

www.mghcme.orgSOURCES: Jalal et al., Science 361, 2018

The Opiate Epidemic

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The Opiate Epidemic

SOURCES: Jalal et al., Science 361, 2018

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Today’s Talk

• Who gets Addicted?

• The Addiction Cycle

–Role of Dopamine/Reward in Addiction

–Role of Impaired Inhibition in Addiction

• Changes in the Brain that Occur

• Treatment and Recovery

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The addiction cycle

Koob and Volkow 2010

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The addiction cycle

Koob and Volkow 2010

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The addiction cycle

Koob and Volkow 2010

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Reward, Dopamine, and the Nucleus Accumbens (NAc)

Reward: stimulus that induces subjective feelings of pleasure.

Rewarding stimuli activate the mesocorticolimbicreward circuit.

All drugs of abuse share the ability to activate the this circuit.

increase extracellular dopamine (DA) levels in the NAc Gilman et al. 2008

Alcohol:

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dopamine

transporters

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Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.

Natural Rewards Elevate Dopamine Levels

0

50

100

150

200

0 60 120 180

Time (min)

% o

f B

asa

l D

A O

utp

ut NAc shell

Empty

Food Sex

Box Feeding

100

150

200

DA

Co

nce

ntr

ati

on

(%

Ba

seli

ne)

Sample

Number

1 2 3 4 5 6 7 8

Female Present

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0

100

200

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600

700

800

900

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1100

0 1 2 3 4 5 hr

% o

f B

asal

Rel

ease

DADOPACHVA

Accumbens

Amphetamine

0

100

200

300

400

0 1 2 3 4 5 hr

% o

f B

asal

Rel

ease DA

DOPACHVA

Accumbens Cocaine

Time After Drug

Morphine

0

100

150

200

250

0 1 2 3 hr

Time After Drug

% o

f B

asal

Rel

ease

AccumbensCaudate

Nicotine

Di Chiara and Imperato, PNAS, 1988

Effects of Drugs on Dopamine Release

% o

f B

asal

Rel

ease

0

100

150

200

250

0 1 2 3 4 5 hr

Accumbens

0.51.02.510

Dose

mg/kgmg/kg

mg/kg

mg/kg

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Reward

o enhanced dopamine in the NA is responsible for acute high or initial reinforcing effects of drugs of abuse.

o Drugs of abuse are able to more rapidly and markedly elevate DA levels to supraphysiological levels for sustained periods of time compared with natural rewards

o Drugs outcompete natural reinforcers and end up “hijacking” and corrupting the initial process of reward processing.

Roberts & Koob, 1980

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Is this Responsible for Addiction?

Behaviors persist despite tolerance to the positive effects of drugs over time

Individuals maintain use of substances through negative reinforcement to avoid negative states such as withdrawal states or to attempt to self- medicate for underlying psychic distress.

Degree of euphoria of a substance does not necessarily predict its addictiveness (i.e. nicotine)

(Berridge et al., 2009)

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The Switch from Reward to Negative Reinforcement/Withdrawal

o enhanced dopamine in the NA is responsible for acute high or initial reinforcing effects (i.e., positive reinforcement) of drugs of abuse.

o All major drugs of abuse activate the brain stress systemso Elevated corticotrophin releasing factor

(CRF) in the amygdala

George, Le Moal, and Koob, 2012

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Executive Function Component

o loss of control, impulsivity, and impaired decision-making capacity

o Involves:o Orbitofrontal cortex (OFC):

assigns a motivational value based on a prediction of reward

o Anterior cingulate (ACC): role in inhibitory control of behaviors

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1) Reward (drive to meet goals) –Strong urge to use drugs over natural rewards, associated with impulsivity

2) Inhibition (control of goal-directed behavior) – Reduced control over behavior despite negative consequences

~Both abnormalities are worsened by stress

Baler & Volkow, 2006; Koob & Volkow 2009

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Inhibition: Just Say No?

Ability to ‘stop’ a response, even when it is habitual and includes:• Motor actions• Higher-order responses

(i.e., thoughts, memories, or emotions)

Critical for stopping both automatic and habitual behaviors to help us meet our goals

Related to impulsiveness in the healthy population

Cools, 2008; Jentsch and Taylor, 1999; Nigg et al2005; Avila and Parcet, 2001; Logan et al., 1997; but see Enticott et al., 2006

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Just Say No??

• Addiction: loss of control over intense urges despite adverse consequences.

The model is:

Greater reinforcing (rewarding) properties of drugs/diminished reinforcement from natural rewards = greater drive to use drugs

Diminished inhibitory control over behavior as evidenced by reduced prefrontal cortical activity during decision-making tasks = greater use of drugs despite serious negative consequences

Volkow & Fowler, 2000; Koob & Volkow, 2010

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Today’s Talk

• Who gets Addicted?

• The Addiction Cycle

– Role of Dopamine/Reward in Addiction

– Role of Impaired Inhibition in Addiction

• Changes in the Brain that Occur

• Treatment and Recovery

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Structural Effects of Addiction

Pfefferbaum et al. 1997

Control brain Alcoholic brain

Gilman et al. 2008

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Reduction in Amygdala Size in Cocaine Users

Makris et al. 2004

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Dopamine Transporters in Methamphetamine Abusers

Normal Control

Methamphetamine Abuser

Motor TaskLoss of dopamine

transporters in

methamphetamine

abusers may result in

slowing of motor

reactions.

Memory TaskLoss of dopamine

transporters in

methamphetamine

abusers may result

in memory impairment.

7 8 9 10 11 12 131.0

1.2

1.4

1.6

1.8

2.0

Time Gait(seconds)

468101214161.0

1.2

1.4

1.6

1.8

2.0

Delayed Recall(words remembered)

Do

pa

min

e T

ran

spo

rter

Bm

ax

/Kd

Volkow et al., Am. J. Psychiatry, 2001.

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Certain brain regions such as the Insula are especially important in the

maintenance of addictive behavior

Navqi et al., Science, 2007

Patients with damage to the INS were able to quit cigarette smoking “easily, immediately, without relapse, and without persistence of the urge to smoke”

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Substance use is particularly damaging to the adolescent brain

• high amounts of alcohol/ cannabis exposure during adolescence:– disrupts

processes of brain maturation

– worsens neurocognitive functioning.

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Today’s Talk

• Who gets Addicted?

• The Addiction Cycle

– Role of Dopamine/Reward in Addiction

– Role of Impaired Inhibition in Addiction

• Changes in the Brain that Occur

• Treatment and Recovery

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Prolonged Drug Use Changesthe Brain In Fundamental

and Long-Lasting Ways

Science Has Generated MuchEvidence Showing That…

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These changes are long-lasting

www.mghcme.orgGerman & Fields, 2006

Morphine-induced CPP: Movement patterns during a 15-min test before and after four pairings of the left compartment with morphine 10 mg/kg,

s.c.

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Morphine CPP: Persistence of effect of drug-paired cuesinfrequent 15-min tests: no drug since training

Note the lack of extinction when test are widely spaced

0

200

400

600

0 2 4 6 8 10 12

Week

Group 1

0 2 4 6 8 10 12

Week

SalineNeutralMorphine

Group 2

Mueller et al., 2000

Compartment

Tim

e in

ch

amb

er

(sec

)

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Who Gets Treatment??

8.3% of Americans have diabetes

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84%

16%

Any diabetes treatment No treatment

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9.5% of Americans have

a mood disorder in a

given year

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41%

59%

Any MH treatment No treatment

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7.4% of Americans have a

substance use disorder in a

given year

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9%

91%

Any addiction treatment No treatment

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WHY?? People can’t afford treatment

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• <1% are current prescribers

• Many psychiatric clinics will not prescribe buprenorphine

Train more psychiatrists?

• <0.01% are prescribers

• Majority of primary care clinics will not prescribe buprenorphine

Train more PCPs?

• About 20-40 new board-certified addiction psychiatrists per year in the US

Train more addiction

psychiatrists?

WHY?? Not enough doctors! (ex: Suboxone)

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Addiction is Similar to Other Chronic Illnesses Because:

• It has biological and behavioral components, both of which must be addressed during treatment.

• Recovery from it--protracted abstinence and restored functioning--is often a long-term process requiring repeated episodes of treatment.

• Relapses can occur during or after treatment, and signal a need for treatment adjustment or reinstatement.

• Participation in support programs during and following treatment can be helpful in sustaining long-term recovery

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Full recovery is a challenge

but it is possible …

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It takes time, but

the brain can

recover

DAT Recovery

with prolonged

abstinence from

methamphetamine

[C-11]d-threo-methylphenidate

Volkow et al., J. Neuroscience, 2001.

low

high

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Conclusions

• Addiction is a brain disease, with both biological and behavioral risk factors

• Addiction consists of specific stages, that each involve different brain regions and different neurotransmitters

• Addiction disrupts brain circuits involved in judgment and decision-making, so that “saying no” becomes very difficult

• These disruptions of brain circuitry are long-lasting• Specific treatments of addiction exist, and those treatments

work to help patients maintain abstinence

• Thank you for your attention!!!